High anti-tumor activity of a novel alpha-fetoprotein-maytansinoid conjugate targeting alpha-fetoprotein receptors in colorectal cancer xenograft model

Abstract

Abstract The alpha-fetoprotein receptor (AFPR) is a novel target for cancer therapeutics. It is expressed on most cancers and myeloid derived suppressor cells (MDSCs) but generally absent on normal tissues. Studies were performed to investigate the use of recombinant human AFP (ACT-101) conjugated with maytansinoid toxins for targeted toxin delivery to cancer. Four structurally different ACT-101-maytansinoid conjugates containing cleavable glutathione sensitive linkers were initially investigated in a mouse xenograft model of colorectal cancer. Reduction in tumor volume was seen for all four conjugates compared to control (p < 0.05). The anti-tumor effects of the conjugate selected for further development (ACT-903) persisted after treatment discontinuation, with tumors becoming undetectable in 9 of 10 mice, and all 10 mice surviving through Day 60 with no obvious signs of toxicity. A follow-up study performed in the same model compared the effects of single intravenous doses of ACT-903 (10–50 mg/kg) to that of control groups receiving vehicle or ACT-101. A significant reduction of tumor burden compared to control was achieved in the 40 and 50 mg/kg dose groups. Survival was significantly prolonged in these 2 groups (40 mg/kg (p < 0.0001); 50 mg/kg (p = 0.0037). Free maytansine blood levels at 4 h were 0.008% of the dose, indicating stability of the conjugate in circulation as was expected based on in vitro plasma stability studies. No obvious signs of toxicity were seen in any of the treated groups. Observed efficacy and excellent tolerability of ACT-903 in these xenograft models support advancing the development of ACT-903 toward clinical use.

Keywords

• Alpha-fetoprotein-maytansinoid conjugate
• Colorectal cancer
• AFP receptor
• Tumor targeting